rs33954691

Positions:

chr5-1255405-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198253.3(TERT):c.3039C>T(p.His1013=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,092 control chromosomes in the GnomAD database, including 12,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 935 hom., cov: 33)

Exomes 𝑓: 0.11 ( 11110 hom. )

Consequence

TERT
NM_198253.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -0.189

Variant links:

Genes affected

TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]

TERT links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 5-1255405-G-A is Benign according to our data. Variant chr5-1255405-G-A is described in ClinVar as [Benign]. Clinvar id is 39119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1255405-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.189 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TERT	NM_198253.3 linkuse as main transcript	c.3039C>T	p.His1013=	synonymous_variant	14/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.2850C>T	p.His950=	synonymous_variant	13/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.2747C>T		non_coding_transcript_exon_variant	11/13
TERT	NR_149163.3 linkuse as main transcript	n.2711C>T		non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.3039C>T	p.His1013=	synonymous_variant	14/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1
	ENST00000666708.1 linkuse as main transcript	n.448G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0940

AC:

14308

AN:

152206

Hom.:

935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.0967

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.104

GnomAD3 exomes

AF:

0.130

AC:

32473

AN:

249236

Hom.:

2681

AF XY:

0.129

AC XY:

17461

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.178

Gnomad SAS exome

AF:

0.164

Gnomad FIN exome

AF:

0.0944

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.115

AC:

167415

AN:

1461766

Hom.:

11110

Cov.:

AF XY:

0.116

AC XY:

84287

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0187

Gnomad4 AMR exome

AF:

0.242

Gnomad4 ASJ exome

AF:

0.120

Gnomad4 EAS exome

AF:

0.253

Gnomad4 SAS exome

AF:

0.165

Gnomad4 FIN exome

AF:

0.0935

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.107

GnomAD4 genome

AF:

0.0939

AC:

14300

AN:

152326

Hom.:

935

Cov.:

AF XY:

0.0976

AC XY:

7270

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0231

Gnomad4 AMR

AF:

0.190

Gnomad4 ASJ

AF:

0.115

Gnomad4 EAS

AF:

0.186

Gnomad4 SAS

AF:

0.158

Gnomad4 FIN

AF:

0.0967

Gnomad4 NFE

AF:

0.103

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.0939

Hom.:

496

Bravo

AF:

0.0975

Asia WGS

AF:

0.160

AC:

555

AN:

3478

EpiCase

AF:

0.0999

EpiControl

AF:

0.104

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	His1013His in exon 14 of TERT: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.1% (862/8526) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs33954691). -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Aplastic anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Dyskeratosis congenita

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Acute myeloid leukemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Dyskeratosis congenita, autosomal dominant 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

4.2

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over